Neutrophil infiltration is a hallmark of pulmonary inflammation during respiratory viral infections, yet the origin of these cells has been a subject of debate. Using a golden hamster model of SARS-CoV-2 infection, the study led by Professor Xuetao Cao's team at the Chinese Academy of Medical Sciences unveiled a dynamic spleen-to-lung neutrophil axis that operates during antiviral defense. Their findings were made available online in Volume 2 of the Immunity & Inflammation journal on March 11, 2026. The team integrated single-cell RNA velocity analysis with spatial transcriptomic deconvolution to track neutrophil dynamics across time and tissues. What emerged was a clear picture of inter-organ crosstalk: at the peak of antiviral response, neutrophils originating from the spleen migrate to the lung, replenishing local pools at various differentiation stages and actively participating in innate immune defense.
The investigation began with a detailed kinetic analysis of lung immune cells. Single-cell RNA velocity profiling of lung tissue at day seven post-infection revealed a unidirectional differentiation trajectory within the neutrophil compartment—from a proliferating subset through immature and mature stages to fully activated cells. Notably, the proliferative and activation phases were temporally and transcriptionally distinct, suggesting that local proliferation alone could not account for the sheer magnitude of neutrophil accumulation.
Between days five and seven post-infection, a marked increase in neutrophil numbers was observed in the spleen, coinciding precisely with the peak of pulmonary infiltration. This temporal synchrony prompted a comparative transcriptomic analysis of neutrophil subsets from both organs. The results were striking: neutrophils from the spleen and lung partitioned into the same three major subsets—proliferative, non-activated, and activated—and within each subset, gene expression profiles were highly similar. This transcriptional similarity strongly suggested that neutrophils accumulating in the spleen during this window were destined for the lung.
To directly test whether splenic cells seed the lung, the team employed spatial transcriptomics data from lung tissue, using the single-cell datasets as references for deconvolution analysis with the Redeconve algorithm. This approach enabled precise localization of cell subsets of different origins within the pulmonary architecture. Among all immune cell types examined, only neutrophils showed a substantial contribution from the spleen. By days five to seven post-infection, the proportion of spleen-derived neutrophils in the lung rivaled or even exceeded that of locally derived cells. In contrast, other immune populations remained predominantly lung-derived, with minimal splenic input.
The influx of splenic neutrophils followed a temporally orchestrated pattern. At day five, early-differentiation proliferative neutrophils of splenic origin were enriched in the lung. By day seven, the dominant subsets shifted to immature and mature/mildly activated splenic neutrophils, indicating a continuous supply chain from progenitor to effector cells.
The directional migration of immune cells relies on precise chemokine-receptor interactions. The team identified the molecular basis for this spleen-to-lung trafficking. At days five to seven post-infection, lung tissue exhibited peak expression of multiple neutrophil-attracting chemokines, including Cxcl5 , Cxcl12 , and Ccl11 . These chemokines were produced by specific lung-resident cell populations—epithelial cells, macrophages, and fibroblasts—each contributing distinct signals.
Simultaneously, splenic neutrophils at different differentiation stages displayed differential chemokine receptor expression. Immature neutrophils preferentially expressed Cxcr4 , the receptor for Cxcl12 , while mature neutrophils upregulated Cxcr2 , Ccr1 , and Ccr3 , which bind Cxcl5 , Ccl11 , and other chemokines. This matching of receptors on migrating cells with ligands produced in the lung creates a chemokine code that guides the precise, stage-specific recruitment of splenic neutrophils to the inflamed organ.
“ This study fundamentally revises the understanding of neutrophil dynamics during respiratory viral infection, ” Prof. Cao pointed out. By integrating single-cell and spatial multi-omics, the team has demonstrated that the spleen functions as an extra-medullary hub for neutrophil mobilization, supplying the lung with a continuous stream of cells at various differentiation stages to meet the demands of antiviral defense. The findings challenge the traditional view that pulmonary neutrophils derive exclusively from local sources or from the bone marrow, revealing instead a coordinated inter-organ network.
“ The identification of the spleen-to-lung neutrophil axis and the chemokine – receptor pairs that govern it opens new avenues for therapeutic intervention, ” the authors highlighted. For inflammatory lung conditions driven by excessive or dysregulated neutrophil responses—including severe viral pneumonia—targeting this axis could offer a means to modulate immune cell recruitment and activity. The study provides a new theoretical framework for understanding inter-organ immune coordination and highlights potential diagnostic and therapeutic targets for pulmonary infectious diseases.
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Reference
DOI: 10.1007/s44466-026-00030-8
About Immunity & Inflammation
Immunity & Inflammation is a newly launched open-access journal co-published by the Chinese Society for Immunology and Springer Nature under the leadership of Editors-in-Chief Prof. Xuetao Cao and Prof. Jules A. Hoffmann. Immunity & Inflammation aims to publish major scientific questions and cutting-edge advances that explore groundbreaking discoveries and insights across the spectrum of immunity and inflammation, from basic science to translational and clinical research.
Website: https://link.springer.com/journal/44466
About Author s
Prof. Xuetao Cao from Chinese Academy of Medical Sciences
Prof. Xuetao Cao is an Academician of the Chinese Academy of Engineering. He serves as the Director of Center for Immunotherapy at the Chinese Academy of Medical Sciences, Chair of the Academic Committee of the National Key Laboratory of Immunity and Inflammation, Chief Scientist of the National Major Project for Innovative Drug Development, and Director of the Institute of Immunology at Nankai University. He has been honored with many awards including the Guanghua Engineering Award from the Chinese Academy of Engineering, the Chen Jia Geng Science Award from the Chinese Academy of Sciences, the Chang Jiang Scholar Achievement Award from the Ministry of Education, and the National Award for Innovation and Dedication. His research focuses on fundamental studies of innate immunity and inflammation, as well as applied research in cancer immunotherapy.
Dr. Zongheng Yang from Chinese Academy of Medical Sciences
Dr. Zongheng Yang is an Assistant Research Fellow in the Department of Immunology at the Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences. His research focuses on deciphering the cellular and molecular mechanisms of immune regulation using single-cell spatial multi-omics technologies.
Funding information
This work was supported by Grants from the National Natural Science Foundation of China (82388201), Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (2024-I2M-ZD-005, 2021-PT310-002 and 2022-I2M-2-001).
Experimental study
Animals
Single-cell spatiotemporal mapping reveals a spleen-to-lung neutrophil axis in antiviral defense
11-Mar-2026
The corresponding author Xuetao Cao is the Editor-in-Chief of the journal Immunity & Inflammation. The authors Bingjing Wang and Shuo Liu are the editors of Immunity & Inflammation. However, they were not involved in the peer-review or decision-making process for this manuscript. The authors declare no other competing interests.